Method of treating disease by auricular anesthesia of cranial nerves

ABSTRACT

Methods for treating a variety of diseases that comprises performing auricular anesthesia of the vagus, facial, trigeminal, or glossopharyngeal nerves, or combinations thereof. A pharmaceutical composition is administered to an ear canal of a subject in need of such treatment, the composition including an analgesic and an anesthetic. Compositions useful in the taught methods are also provided.

This application claims benefit of and priority to U.S. ProvisionalApplication No. 61/819,023, filed May 3, 2013, by Thomas M. Crews, andis entitled to that filing date for priority. The specification, figuresand complete disclosure of U.S. Provisional Application No. 61/819,023are incorporated herein by specific reference for all purposes.

FIELD

The present disclosure relates to methods for treating a variety ofdiseases by performing auricular anesthesia of the fifth cranial nerve(trigeminal nerve), the seventh cranial nerve (facial nerve), ninthcranial nerve (glossopharyngeal nerve), and the tenth cranial nerve(vagus nerve).

BACKGROUND

The vagus nerve, also known as cranial nerve X, is the tenth of twelvepaired cranial nerves and is the longest of the cranial nerves. Uponleaving the medulla between the medullary pyramid and the inferiorcerebellar peduncle, it extends through the jugular foramen, then passesinto the carotid sheath between the internal carotid artery and theinternal jugular vein down below the head, to the neck, chest andabdomen, where it contributes to the innervation of the viscera. Theanatomy of the vagus nerve is illustrated in FIGS. 1 and 2.

Upon exiting the jugular foramen, the vagus nerve forms the jugularganglion and the ganglion nodosum or the superior and inferior vagalganglion. The jugular ganglion is joined by filaments from the petrousganglion of the glossopharyngeal nerve. The auricular branch of thevagus nerve also has connections from the jugular ganglion of ten andthe petrous ganglion of the glossopharyngeal nerve as it enters themastoid canaliculus from the lateral wall of the jugular fossa. Brushingthe temporal bone, the auricular branch of vagas exits thetympanomastoid fissure and divides into two branches; one joins thepost-auricular nerve and the other is distributed to the skin of theback of the ear and to the posterior external acoustic meatus.

The vagus nerve conveys sensory information about the state of thebody's organs to the central nervous system. Approximately 80% of thenerve fibers in the vagus nerve are afferent, or sensory nerves,communicating the state of the viscera to the brain, while the remaining20% are efferent, or functional nerves.

The vagus nerve is responsible for regulating a host of bodilyfunctions, including, but not limited to, breathing, speech, sweating,facilitating in keeping the larynx open during breathing, monitoring andregulating heartbeat, and digestion of food in the stomach, along with ahost of other physiological functions.

Consequently, manipulation of the vagus nerve and subsequent alterationof its normal physiological function may have profound effects upon awide range of human ailments that are associated with vagus nerveregulation. However, the present procedures available in the art foraltering the function of the vagus nerve are highly invasive. Thesecurrent procedures often rely upon the implantation of artificialmechanical devices into the body of a patient. Besides being highlyinvasive surgical procedures, these methods are very costly.

For instance, the United States Food and Drug Administration approved aprocedure called vagus nerve stimulation (VNS) in the late 1990s for thetreatment of partial onset epilepsy. VNS is performed as a surgicalprocedure to install a pacemaker-like device into a subject sufferingfrom epileptic seizures. The device, implanted inside a patient's neckarea, is used to send mild electrical impulses through the vagus nerve.The device is battery operated, and has an electrical pulse generator.After it is implanted, electrodes with insulated plastic are run intothe vagus nerve from under the skin on the patient's neck. The pulse isset to operate alternately, by turning on every few seconds and thenturning off.

Researchers have also begun to investigate the possibility of utilizingthese pacemaker-like devices in the stomach of obese patients to blockthe function of the vagus nerve, in order to suppress appetite. Again,these procedures are highly invasive and involve the implantation ofartificial devices into the body of a patient.

Some surgeons have even performed vagotomy procedures to treat obesity.In these procedures, the surgeon completely severs a patient's vagusnerve. While these procedures successfully allowed the subjects to loseweight, it is apparent that such an invasive and permanent surgicalprocedure is problematic for many patients.

Cranial nerve seven or the facial nerve is one of the twelve pairedcranial nerves (see FIG. 3). It is so named because its main function isto supply motor innervation to the muscles of the face. Other muscles itinnervates are the platysma, the posterior belly of the digastric, andthe stapedius muscle. The sensory and parasympathetic portion of thefacial nerve travels in the nervus intermedius and supplies thefollowing components: (1) taste to the anterior two-thirds of thetongue; (2) secretory and vasomotor fibers to the lacrimal gland, themucus glands of the nose and sinuses, mouth, and the submandibular andsublingual salivary glands; and (3) cutaneous sensory impulses from theexternal auditory meatus and regions of the back of the ear. It is alsothought that a parasympathetic impulse from the nervus intermedius, tothe sphenopalatine ganglion, to the mucosa and submucosa of the nose andparanasal sinuses determines their venous capacitance and level ofcongestion.

The parasympathetic portion of the seventh cranial nerve takes itsorigin in the nucleus salivatorius in the brain stem and enters theinterior acoustic meatus separate from the motor division of the facialnerve. It combines with the facial nerve proximal to the geniculateganglion. The fibers leave the geniculate ganglion through the greatsuperficial petrosal nerve and are joined by the large deep petrosalnerve to form the vidian nerve, or the nerve of the pterygoid canal,where together they move forward to synapse in the sphenopalatineganglion. There they provide parasympathetic innervation to the eye,nose, sinus, palate, pharynx, and salivary glands. The geniculateganglion receives general somatic afferent fibers from the externalauditory canal via the auricular branch of the vagus nerve and itsconnection to the seventh cranial nerve. General somatic sensoryafferent fibers synapse in the geniculate ganglion.

The trigeminal nerve or the fifth cranial nerve is the fifth of twelvepaired cranial nerves and is the largest of all the cranial nerves (seeFIG. 4). It is the great sensory nerve of the skin of the face, scalp,ear canal, the mucus membranes and other internal structures of thehead. It also has functions as motor innervation to the muscles ofmastication and contains proprioceptive fibers. It further carriessensory innervation from the dura of the brain with its variousbranches. The fifth cranial nerve is quite extensive. The main sensorynucleus extends from the pons to the upper spinal cord. The nucleusreceives its afferent fibers from the semi-lunar ganglion, also known asthe Trigeminal ganglion or the Gasserian ganglion. The Trigeminalganglion contains the cell bodies of the sensory fibers for its threemain divisions. It receives three large sensory division: theophthalmic, maxillary, and mandibular divisions. The sensory root fibersleave the ganglion posteriorly to pass their insertion into the pons.

The glossopharyngeal nerve, also known as the ninth cranial nerve, isthe ninth of twelve paracranial nerves that is known as the tympanicnerve and has both sensory and secretory fibers (see FIGS. 5 and 6). Thenerve is a mixed sensory and motor nerve. The sensory component consistsof somatic afferent fibers supplying sensation to the mucus membranes ofthe pharynx and tonsillar region and back of the tongue. The superficialorigin of the glossopharyngeal nerve from the brain stem is by three orfour rootlets in the groove between the olive and the inferior peduncle.It exits the skull through the jugular foramen and runs anteriorlybetween the internal carotid artery and the internal jugular vein. Uponexiting the jugular foramen, it forms a pair of ganglionic swellings:the superior or jugular ganglion, and the inferior or petrosal ganglion.The ganglion contains cell bodies of the sensory fibers of the nerve.The ninth nerve communicates with the vagus nerve or the tenth cranialnerve, the facial nerve, and the sympathetic ganglion.

The glossopharyngeal nerve has five distinct general functions: (1)motor (special visceral efferent) supplies the stylopharyngeus muscle;(2) visceral motor (general visceral efferent) provides parasympatheticinnervation of the parotid gland; (3) visceral sensory (general visceralafferent) carries visceral sensory information from the carotid sinusand carotid body; (4) general sensory (general somatic efferent)provides general sensory information from the skin of the external ear,internal surface of the tympanic membrane, upper pharynx, and posteriorone-third of the tongue; and (5) special sensory (special afferent)provides taste sensation from the posterior one-third of the tongue,including circumvallate papillae.

Thus, there is a great need in the medical community for methods oftreating vagus and other cranial nerve associated diseases that are notdependent upon altering the function of the vagus nerve or other cranialnerves through invasive surgical procedures or artificial devices.Specifically, there is a great need in the art for procedures to alterthe function of the vagus and other cranial nerves that arenon-invasive, safe, effective, and economical.

SUMMARY OF THE INVENTION

In various embodiments, the present invention provides a safe andnon-invasive procedure, by which to treat a host of human diseases, andtheir symptoms, that are associated with the fifth cranial nerve(trigeminal nerve), the seventh cranial nerve (facial nerve), ninthcranial nerve (glossopharyngeal nerve), and the tenth cranial nerve(vagus nerve). The present disclosure provides a method of disruptingthe normal physiological function of the nerve that does not rely uponan invasive and costly surgical procedure. The disclosed methods areable to “block” the transduction of both afferent and efferent signalsfrom being transmitted via the trigeminal, facial, glossopharyngeal orvagus nerves. Such blockage of the transduction of signals on the nerveis achieved by a topical auricular anesthesia procedure, whereby apharmaceutical composition is administered to the ear canal of asubject. It is the cutaneous auricular anesthesia of those nerves andtheir particular close proximity and relationship to their respectiveganglia that allows for their modulation in function. It is thatmodulation of function which results in the modulation of expression ofspecific disease processes.

In an exemplary embodiment, the present disclosure provides a method fortreating symptoms of a disease, which comprises topically administeringto an ear canal of a subject a pharmaceutical composition, comprising:(i) an analgesic and (ii) an anesthetic. In an embodiment, the analgesicis at least one pyrazolone derivative selected from the group consistingof ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone. In apreferred embodiment, the analgesic is antipyrine. In an embodiment, theanesthetic is at least one selected from the group consistingbenzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine,larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine,tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine,etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine,prilocalne, ropivacaine, trimecaine, and pharmaceutically acceptablederivatives thereof. In a preferred embodiment, the anesthetic isbenzocaine.

The diseases that are treatable by the disclosed methodology arenumerous. Any disease that is associated with an organ or bodily tissuethat is innervated by the particular nerve could potentially be treatedby the present methods. Particular mention of the following diseasestreatable by the present methods is made: asthma, neurogenic cough,globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease,and obesity. The present methods are also suitable for treatingpost-tonsillectomy or post-adenoidectomy pharyngeal pain, ororopharyngeal pain.

In yet other embodiments, the diseases treatable by the disclosedmethodology include, but are not limited to: cardiac diseases,paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope,postural orthostatic tachycardia syndrome (POTS), excessive gag reflex,esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain,esophageal neuralgia, gastritis, dyspepsia, gall bladder disease,colecistitis pain, abdominal pain, esophageal motility disorder oresophageal dysmotility, spastic colon, pancreatic pain or spasms,pediatric colic, rectal spasms and pain, bladder spasm (overactivebladder), interstitial cystitis, dysmenorrhea, premature labor, pelvicpain, chronic pelvic pain, chronic prostatitis pain, eclampsia,preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome,Cohn's disease, ulcerative colitis, reflux disease, gastritis,gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic,hepato-renal syndrome, appetite suppression, gall bladder pain,inflammation of the esophagus, inflammation of the stomach, inflammationof the colon, kidney pain (from stone, infection, or tumor), enuresis,dysuria, dyspareunia, encopresis, heavy flow periods, frequenturination, prolonged vaginal bleeding, inhibit erections, prevention ofpremature ejaculation, inhibit excessive sweating, ureteral spasms,menstrual cramps, uterine spasms, ovarian pain and spasms, fallopiantube pain and spasms, pediatric asthma, adult asthma, chronicobstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis,asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis,inflammation of the lung, emphysema, pleuritic chest pain, intercostalmuscle pain, nerve pain, bronchospasm secondary to intubation andextubation, angina pectoris, cardiac vagal blockage, vasovagal reflexblockage, bradycardia, hypotension, orthostatic hypotension,hypertension, diabetes, shock, septic shock, reduction of blood sugar,inflammation of the pancreas, syncope secondary to vagal or cardiacreasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin,neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chroniclaryngitis, post extubation and intubation laryngospasms, palatalmyoclonus, post-tonsillectomy pain, snoring, allergic rhinitis,vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis,chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups,rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome,fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panicattacks, post-traumatic stress disorder, Tourette's syndrome, focaldystonia, tic doloreaux, bulimia, anxiety, depression, restless legsyndrome, dysautonomia, familial intentional tremor, migraines, autismspectrum, anxiety headaches, insomnia or sleep disorders, multiplesclerosis, modulation of the reticular activating system, peripheralneuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

Thus, it is apparent that the present method applies generally to thetreatment of any disease, ailment, or bodily condition that may benefitfrom the “blockage” of the particular nerve function. That is, anycondition that would benefit from the hampered ability of the nerve totransmit neurological signals are encompassed by the disclosed method.

In methods disclosed herein, the pharmaceutical composition isadministered to the ear canal of a subject in a concentration sufficientto physiologically alter the activity of the subject's nerve compared tothe physiological activity of a nerve in a subject not administered thepharmaceutical composition. Thus, the present pharmaceutical compositionutilized in a method as disclosed, is able to disrupt the naturalability of the nerve to transmit neurological signals along its length.These signals, both afferent and efferent, are blocked or hampered bythe present methods.

The amount of analgesic present in the pharmaceutical composition mycomprise from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg permL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to100 mg per mL, or 100 mg per mL. In some embodiments, the amount ofanalgesic present is from about 50 to 60 mg per mL, or about 54 mg permL, or about 50 to 55 mg per mL, or about 55 to 60 mg per mL.

The amount of anesthetic present in the pharmaceutical composition mycomprise from about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL, 50 to 100 mg permL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to100 mg per mL, or 100 mg per mL. In some embodiments, the amount ofanesthetic present is from about 1 to 20 mg per mL, or about 1 to 15 mgper mL, or about 5 to 15 mg per mL, or about 10 to 20 mg per mL, orabout 10 to 15 mg per mL, or about 14 mg per mL.

The total amount of the pharmaceutical composition administered to apatient during one dosage may comprise from about: 0.001 to 0.01 mL ofsolution, or 0.01 to 0.1 mL of solution, or 0.1 to 0.5 mL of solution,or 0.1 to 1 mL of solution, or 1 to 1.5 mL of solution, or 1.5 to 2 mLof solution, or 2 to 5 mL of solution, or 5 to 10 mL of solution. Theadministration may comprise using a “dropper” bottle that applies“drops” of solution to the patients ear canal during a typical dosage.Such administration may comprise 1 mL≈15-20 drops, 0.5 mL≈10 drops, 0.25mL≈5 drops.

As used herein, unless otherwise expressly specified, all numbers suchas those expressing values, ranges, amounts, or percentages may be readas if prefaced by the word “about,” even if the term does not expresslyappear. Any numerical range recited herein is intended to include allsub-ranges subsumed therein. Plural encompasses singular and vice versa;e.g., the singular forms “a,” “an,” and “the” include plural referentsunless expressly and unequivocally limited to one referent.

In certain embodiments, the subject treated by the present methods doesnot have an ear infection. Furthermore, in certain embodiments, thesubject treated by the present methods does not have an ear ache or isnot experiencing ear pain.

In particular aspects, the present method is not utilized on patientswith ear infections. That is, the present methods, in certainembodiments, specifically exclude utilization on patients with an earinfection or ear pain associated with an ear infection. Certainembodiments specifically exclude utilizing the method on subjectsexperiencing an ear ache or ear pain. In these embodiments, a first stepof the method may comprise an ear examination by a treating physician toassure that the patient does not have ear pain, or an ear ache, orswelling of the tissue in the ear that may cause ear pain, or an earinfection. In some aspects, after the ascertainment that a patient doesnot have any of the aforementioned, the patient's ear canal may betreated with the disclosed pharmaceutical composition, which in apreferred embodiment comprises antipyrine and benzocaine.

The disclosed pharmaceutical compositions utilized in the presentmethods may comprise additional components such as: antibiotics,vasoconstrictors, glycerin, and acetic acid.

The pharmaceutical compositions may comprise any pharmaceuticallyacceptable carrier, or adjuvant, and may be formulated as: solutions,foams, gels, creams, pastes, lotions, emulsions, and combinations of theaforementioned.

The pharmaceutical composition may be administered once a day, twice aday, three times a day, four times a day, five times a day, six times aday, seven times a day, eight times a day, nine times a day, 10 to 20times a day, or up to continuously throughout the day as needed.Further, in certain embodiments, the pharmaceutical composition isadministered upon the onset of an asthma attack. In other embodiments,the pharmaceutical composition is administered upon a person feelinghungry. Some aspects of the methods entail administration of thepharmaceutical composition upon a patient feeling pain in theirpharyngeal region. Certain embodiments contemplate not utilizing thetaught compositions on patients that are experiencing ear pain, or thathave an ear infection, or swelling in the ear associated with an earinfection. In these embodiments, the disclosed method of treatingdiseases associated with the vagus nerve may be immediately halted orstopped upon a patient developing ear pain.

A specifically preferred ailment to be treated by the disclosed methodis the pharyngeal or oropharyngeal pain associated with a post-operativetonsillectomy or a post-operative adenoidectomy. These embodiments treatpain that patients feel after the aforementioned surgical procedures. Inthese embodiments, the pharmaceutical composition is applied to the earcanal of a subject that has had a tonsillectomy or adenoidectomy within:the preceding 168 hours (or 7 days), preceding 48 hours, preceding 24hours, preceding 12 hours, preceding 4 hours, or immediatelypost-operation, prior to administering the pharmaceutical composition.Thus, the present method contemplates doctors prescribing the disclosedprocedure and pharmaceutical composition to patients to utilizeimmediately upon feeling pain in the pharyngeal or oropharyngeal regionspost-surgery.

Another particularly preferred ailment, or disease, to be treated by thedisclosed method is asthma. In certain embodiments, acute asthma attacksare treated by the present methods. These embodiments involveadministering the pharmaceutical composition to the ear canal of asubject that is presently experiencing an acute asthma attack. Further,these embodiments may comprise treatment of a subject that hasexperienced an asthma attack in the last 48, 24, 12, 6, or 1 hours.Thus, the methods taught herein may be used in conjunction with normalbronchodilators and corticosteroids for the treatment and management ofa patient's asthma. The methods may be suitable for use on asthmapatients experiencing a peak expiratory flow rate (PEFR) of 50 to 79% ofthe patient's normal peak flow readings, i.e. “the yellow zone” asclassified by the American Lung Association. The methods are alsosuitable for use on a patient experiencing a peak expiratory flow rateof less than 50% of the patient's normal peak flow reading, i.e. “thered zone.” The methods can be utilized in conjunction with a rescueinhaler when a patient experiences a severe asthma attack. Consequently,in some embodiments, the present pharmaceutical composition is acomponent of a kit, wherein said kit comprises a rescue inhaler and apharmaceutical composition comprising antipyrine and benzocaine. The kitis intended to be kept with a patient that is in danger of suffering asevere asthma attack. Further, in some embodiments, the pharmaceuticalcomposition is part of an emergency first aid kit that is kept in schoolclassrooms, for example. In these embodiments, teachers could utilizethe present pharmaceutical composition in times of emergency, such aswhen a student suffers a severe asthma attack, but yet there is norescue inhaler readily available.

The present methods are also suitable for use in treating chronicasthma. In these embodiments, patients utilize the disclosedcompositions as taught in the present disclosure to prevent the onset ofan acute asthma attack. In these methods, chronic asthma is managed bycontinuous use of the present methods. Thus, in certain embodiments,patients with asthma are administered the pharmaceutical compositionspresented herein before the onset of an asthma attack. For example,certain embodiments of the present methods are effective at controllingasthma in patients that play sports. Often, patients suffering fromasthma will experience a decreased ability to breathe upon physicalexertion, which in some cases may lead to a severe asthma attackrequiring the use of an inhaler. The present methods allow the treatmentof a subject's ear canal with a pharmaceutical composition comprisingantipyrine and benzocaine before the subject engages in playing a sport.In this manner, the present methods may be an effective therapy forpatient's to utilize before engaging in physical activity, in order toreduce the likelihood of having an asthma attack.

Another particularly preferred condition, or disease, to be treated bythe disclosed method is obesity. The present methods treat obesity byproviding a mechanism to suppress a patient's appetite. By suppressing apatient's appetite, the present methods provide another tool fordoctor's to utilize in managing a patient's weight. Thus, obesity may betreated by administering the taught pharmaceutical composition to asubject's ear canal. In some embodiments, subjects are treated with thetaught pharmaceutical composition whenever the subjects experience asensation of hunger. Further, some embodiments administer the disclosedpharmaceutical compositions to the subject's ear canal immediatelybefore a meal is eaten, or 10 minutes to 60 minutes before a meal iseaten, or 20 to 60 minutes before a meal is eaten, or 30 to 60 minutesbefore a meal is eaten, or concurrently with the consumption of a food.Thus, in some aspects, the present method of auricular anesthesia of thevagus nerve is utilized on a patient within an hour prior to the patienteating any food. In this way, the patient's appetite is satiated andless food will be consumed. Further, some embodiments administer thedisclosed pharmaceutical compositions to the subject's ear canal in themorning, preferably before the subject eats breakfast, thus providing aneffective appetite suppressant that lasts until at least lunch.

In some embodiments, the present pharmaceutical compositions andtreatment methodology are part of a comprehensive weight loss programthat involves not only utilization of the pharmaceutical composition tocurb a patient's appetite, but also may include a specific diet andexercise regime.

In some aspects, a person applying the topical pharmaceuticalcomposition to a patient's ear canal should have good light, so as toget a superficial look into the patient's ear, so as to check for anygross obstructions, i.e. wax, skin, infection, purulence, or swelling.The person may gently pull the ear pinna outward and upward, so as tostraighten out the ear canal. Ear drops comprising the taughtpharmaceutical composition that have been previously warmed and arequite viscid should be applied to the posterior or back wall of thelateral ear opening. The drops should be applied very slowly anddeliberately, one drop at a time, allowing for each drop to slowlymigrate down the ear canal. The patient's head should be resting on itsside on a flat soft surface for optimal application. The back wall ofthe canal and eardrum have a large portion of the vagal nerve fibers,and thus pointed application to this area is desired. In some aspects,children under 10 will require 4 to 8 drops per ear, while adults andchildren over 12 usually require 6 to 10 drops for anesthesia. In someembodiments, drops are always followed by a cotton ball in the lateralear canal for about one hour to insure the maintenance of the medicinein the ear canal to provide the required topical anesthesia to the vagusnerve. After an hour the cotton may be removed.

The administration of a pharmaceutical composition to a patient's earcanal for the purpose of auricular anesthesia of the vagus nerve totreat a disease affected by vagus nerve physiological alteration isreferred to in some embodiments as the “Crews Maneuver.” The CrewsManeuver of utilizing the ear canal as a conduit to anesthetizing thevagus nerve does not suffer from the drawbacks present in the art.

These and other features, aspects, and advantages of embodiments of thepresent disclosure will become better understood with regard to thefollowing description, claims, and accompanying drawings explainedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the complex anatomy of the vagus nerve. Theauricular branch is noted.

FIG. 2 is an illustration of the complex anatomy of the vagus nerveshowing the innervation of the parasympathetic division on one side ofthe body.

FIG. 3 is an illustration of the anatomy of the facial nerve.

FIG. 4 is an illustration of the anatomy of the trigeminal nerve.

FIG. 5 is an illustration of the anatomy of the glossopharyngeal nerve.

FIG. 6 is an illustration of the glossopharyngeal nerve.

FIG. 7 is an illustration of the interior of a human ear. The ear canalis noted.

DETAILED DESCRIPTION

Detailed descriptions of one or more preferred embodiments are providedherein. It is to be understood, however, that the present disclosure maybe embodied in various forms. Therefore, specific details disclosedherein are not to be interpreted as limiting, but rather as a basis forthe claims and as a representative basis for teaching one skilled in theart to employ the present disclosure in any appropriate manner.

A. Disruption of the Transduction of Neurological Signals Along theCranial Nerves

The tenth cranial nerve (vagus nerve) is associated with numerous bodilyorgans and alteration of its normal physiological function can haveprofound effects on a host of human ailments. That is, by “blocking” or“disrupting” or “numbing” the conduction of neurological signals in theparticular nerve, one is able to influence a host of organs that areinnervated by that nerve. Consequently, blocking the transduction ofsignals transmitted along the nerve, whether those signals are afferentor efferent in nature, will alter the normal physiological response ofvarious organs and tissues. This, in turn, can have profoundimplications for treating a variety of diseases, or ailments, that areassociated with human organs and tissues that are innervated by theparticular nerve.

Auricular anesthesia of the cutaneous portion of the seventh cranialnerve (facial nerve) carry signals back to the geniculate ganglion whereparasympathetic fibers and sensory fibers are anesthetized, blocked, orotherwise modulated. Anesthesia of the geniculate ganglion and itsconnection to the Sphenopalatine ganglion serve to modulate or blocktransduction of efferent signals through the facial nerve. This canprofoundly affect disease processes such as, but not limited to,allergic rhinitis, vasomotor rhinitis, inflammatory nasal polyposis,chronic sinusitis, chronic nasal congestion, allergic conjunctivitis,sneezing, and rhinitis in all forms.

The sensory aspect of the fifth cranial nerve (trigeminal nerve) dealswith information from the dura, the mucus membranes of the eyes, themucus membranes of the nose and sinuses, the skin of the externalauditory canal eardrum. Auricular anesthesia of the skin of the earcanal then signals to the trigeminal ganglion via the auriculotemporalbranch of the mandibular division of the trigeminal nerve. Modulation ofafferent signals through the trigeminal ganglion has profound effects onmultiple disease processes. Modulating those afferent signals from thedura, the eye, the nose and sinuses leads to modulation of variousdisease processes. Manipulation of dural signals that pass through theophthalmic, maxillary, and mandibular divisions have profound effects inthe treatments of headaches and migraine headaches. Manipulation ormodulation or blockage of afferent signals from the ophthalmic andmaxillary divisions of the trigeminal nerve will result in modulatedefferent signals from the motor division of the seventh cranial nervethat deal with allergic rhinitis, vasomotor rhinitis, all forms ofrhinitis, inflammatory nasal polyposis, chronic sinusitis, chronic nasalcongestion, allergic conjunctivitis and sneezing.

Auricular anesthesia of the cutaneous portion of the ninth cranial nerve(glossopharyngeal nerve) and its proximity to the petrous ganglion andits connection to the seventh cranial nerve and tenth cranial nerve canhave profound effect on certain disease processes. Because of neuralconnections between the glossopharyngeal nerve and those of the seventhand tenth cranial nerves, disease processes specific to those nerves mayalso be modulated. Diseases specific to the glossopharyngeal nerve thatmay be affected by topical auricular anesthesia include, but are notlimited to, pharyngeal pain, post tonsillectomy pain, sneezing, andparotid salivation.

Thus, several embodiments of the present invention comprise a methodthat blocks the transduction of efferent signals via the vagus,trigeminal, facial, or glossopharyngeal nerves. Another embodiment ofthe disclosure blocks the afferent transduction of signals vi via thevagus, trigeminal, facial, or glossopharyngeal nerves. The presentdisclosure also provides a methodology by which both the afferent andefferent signal transduction via the vagus, trigeminal, facial, orglossopharyngeal nerves is blocked.

B. Pharmaceutical Composition

The methods of the present disclosure utilize the application of apharmaceutical composition to the ear canal of subject in need of suchtreatment. The ear canal is illustrated in FIG. 7. The pharmaceuticalcompositions comprise an analgesic and an anesthetic.

The analgesic present in embodiments of the disclosure are pyrazolone(C₃H₄N₂O) derivatives. The molecular structure of 3-pyrazolone is asfollows:

Derivatives of the isomeric form 5-pyrazolone are also encompassed bythe disclosure.

Particular embodiments of the present methods utilize antipyrine as thepyrazolone derivative. Antipyrine (C₁₁H₂N₂O) is also referred to asphenazone. The molecular structure of antipyrine is as follows:

The anesthetic present in some embodiments of the disclosure are esterbased anesthetics. In a particular embodiment, the anesthetic isbenzocaine (C₉H₁₁NO₂), the molecular formula of which is as follows:

Further embodiments of the method utilize amide based anesthetics.

In a preferred embodiment of the present methods, the disclosedpharmaceutical compositions comprise antipyrine as the analgesic andbenzocaine as the anesthetic.

The pharmaceutical compositions may be formulated in a host of ways,including, but not limited to, the following: solutions, foams, gels,creams, pastes, lotions, emulsions, and combinations of theaforementioned.

Furthermore, the present disclosure contemplates that active ingredientsof the pharmaceutical composition, such as antipyrine and benzocaine,may be infused into material that is then placed into a patient's earcanal. For instance, cotton gauze material could be composed to containthe present pharmaceutical composition, said gauze providing aconvenient application method by which to expose the ear canal to thepresent pharmaceutical composition.

C. Anatomical Site of Application of the Pharmaceutical Composition

The present method contemplates applying the disclosed pharmaceuticalcomposition to the ear canal of a patient. It has been found that theear canal serves as a convenient point in the human anatomy in which toapply the present pharmaceutical composition and achieve disruption ofneurological signals along the vagus or other cranial nerves. That is,by placing a pharmaceutical composition, as described herein, into theear canal of a patient, it has been discovered that the body will absorbthe composition and the vagus or other cranial nerve will be “blocked,”such that the normal physiological function of the nerve will bealtered. The present methodology of utilizing the ear canal as a conduitto anesthetizing the particular nerve does not suffer from the drawbackspresent in the prior art.

The present methods of applying a pharmaceutical composition asdescribed are not invasive and do not pose the risks associated withsurgical procedures. Furthermore, the present methods do not rely uponinserting artificial devices into the body of patient. It is evidentthat the present methods represent a significant advancement over thestate of the art, as the disclosed non-invasive procedure is able toalter the function of the vagus or other cranial nerve withoutartificial devices or surgery. The present methods are also economicaland would therefore provide access to treatment to the vast majority ofa population.

The presently disclosed embodiments of a method of blocking signaltransduction upon the vagus nerve will now be further elaborated upon byreference to the following examples. In each of these examples, thedisclosed method was able to successfully treat a human disease, orailment, that was associated with a particular cranial nerve. That is,the conditions treated in the following example were able to becontrolled to a clinically effective degree by the disclosed method ofperforming auricular anesthesia on the vagus or other cranial nerve,i.e. the “Crews Maneuver.”

EXAMPLES Example 1 Treatment of Post-Tonsillectomy Pharyngeal orOropharyngeal Pain

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering frompost-tonsillectomy pharyngeal, or oropharyngeal pain.

500 patients that had previously undergone a tonsillectomy wereinstructed to utilize six drops of a pharmaceutical compositioncomprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each earthree times per day, for a duration of ten days after the tonsillectomy.

B. Results

Out of the 500 patients treated, 495 patients reported significantreduction in pharyngeal and/or oropharyngeal pain.

Example 2 Treatment of Post-Adenoidectomy Pharyngeal or OropharyngealPain

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering frompost-adenoidectomy pharyngeal, or oropharyngeal pain.

200 patients that had previously undergone an adenoidectomy wereinstructed to utilize six drops of a pharmaceutical compositioncomprising antipyrine (≈54.0 mg) and benzocaine (≈14.0 mg), in each eartwo times per day, for a duration of seven days after the adenoidectomy.

B. Results

Out of the 200 patients treated, 200 patients reported significantreduction in pharyngeal and/or oropharyngeal pain.

Example 3 Treatment of Asthma

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromchronic asthma and acute asthmatic attack.

10 patients with asthma were instructed to utilize six drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg), in each ear in the morning, for two months.

A patient suffering from a severe acute asthma attack was also treatedby immediately filling the patient's ear canal with the aforementionedpharmaceutical composition.

B. Results

Out of the 10 patients treated, 10 patients reported significantreduction in asthmatic attacks.

Further, the patient suffering from the severe asthma attack experienceda dramatic increase in the amount of oxygen reaching his lungs within 60minutes of the treatment.

Example 4 Treatment of Obesity (i.e. a Method of Appetite Suppression)

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromobesity.

5 overweight patients were instructed to utilize six drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg), in each ear in the morning, for an indefiniteperiod of time.

B. Results

Out of the 5 patients treated, all 5 patients reported significantreduction in appetite while utilizing the treatment. The significantreduction in appetite led to weight loss.

Example 5 Treatment of Neurogenic Cough

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromneurogenic cough.

4 patients suffering from neurogenic cough were instructed to utilizesix drops of a pharmaceutical composition comprising antipyrine (≈54.0mg) and benzocaine (≈14.0 mg), in each ear two times per day, for aduration of seven days and then only as needed.

B. Results

Out of the 4 patients treated, all 4 patients reported significantreduction in cough.

Example 6 Treatment of Globus Hystericus

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromglobus hystericus.

2 patients suffering from globus hystericus were instructed to utilizesix drops of a pharmaceutical composition comprising antipyrine (≈54.0mg) and benzocaine (≈14.0 mg), in each ear one time per day, for anindefinite period of time as needed.

B. Results

Out of the 2 patients treated, all 2 patients reported significantreduction in throat tightness.

Example 7 Treatment of Spasmodic Dysphonia

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromspasmodic dysphonia.

1 patient suffering from spasmodic dysphonia was instructed to utilizesix drops of a pharmaceutical composition comprising antipyrine (≈54.0mg) and benzocaine (≈14.0 mg), in each ear one time per day, for anindefinite period of time as needed.

B. Results

The patient reported significant reduction in throat hoarseness andvocal cord spasms almost immediately upon using the treatment.

Example 8 Treatment of Laryngeal Pain

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromlaryngeal pain.

2 patients suffering from laryngeal pain were instructed to utilize sixdrops of a pharmaceutical composition comprising antipyrine (≈54.0 mg)and benzocaine (≈14.0 mg), in each ear one time per day, for anindefinite period of time as needed.

B. Results

Out of the 2 patients treated, all patients reported significantreduction in laryngeal pain.

Example 9 Treatment of Gastroesophageal Reflux Disease

A. Protocol

A test of a preferred embodiment of the present method was conducted toevaluate the efficacy of the method for treating patients suffering fromGastroesophageal Reflux Disease (GERD).

2 patients suffering from GERD were instructed to utilize six drops of apharmaceutical composition comprising antipyrine (≈54.0 mg) andbenzocaine (≈14.0 mg), in each ear one time per day, for an indefiniteperiod of time as needed.

B. Results

Out of the 2 patients treated, all 2 patients reported significantreduction in acid reflux and heartburn.

The results from the aforementioned clinical experiments can be foundbelow in Table 1.

TABLE 1 Number of Subjects % of Subjects Treatment Exhibiting ExhibitingNumber of Protocol Amount Clinical Clinical Subjects (1 mL ≈ of TimeImprovement Improvement Disease Treated Treated 15-20 drops) Treated inSymptoms in Symptoms Post- 500 6 drops per For 10 495  99% Tonsillectomyear 3 times days post Pharyngeal or per day operation Oropharyngeal PainPost- 200 6 drops per For 7 200 100% Adenoidectomy ear 2 times days postPharyngeal or per day operation Oropharyngeal Pain Asthma 10 6 drops perFor 2 10 100% ear in the months morning Obesity via 5 6 drops per Daily5 100% Appetite ear in the Suppression morning Neurogenic 4 6 drops per7 days 4 100% Cough ear 2 times and then per day as needed Globus 2 6drops per As 2 100% Hystericus ear once a needed day Spasmodic 1 6 dropsper As 1 100% Dysphonia ear once a needed day Laryngeal Pain 2 6 dropsper As 2 100% ear once a needed day Gastroesophageal 2 6 drops per As 2100% Reflux Disease ear once a needed (GERD) day

The diseases that are treatable by the disclosed methodology arenumerous. Any disease that is associated with an organ or bodily tissuethat is innervated by the particular nerve could potentially be treatedby the present methods. Particular mention of the following diseasestreatable by the present methods is made: asthma, neurogenic cough,globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease,and obesity. The present methods are also suitable for treatingpost-tonsillectomy or post-adenoidectomy pharyngeal pain, ororopharyngeal pain.

In yet other embodiments, the diseases treatable by the disclosedmethodology include, but are not limited to: cardiac diseases,paroxysmal (lone) (vagal) atrial fibrillation, reflex systolic syncope,postural orthostatic tachycardia syndrome (POTS), excessive gag reflex,esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain,esophageal neuralgia, gastritis, dyspepsia, gall bladder disease,colecistitis pain, abdominal pain, esophageal motility disorder oresophageal dysmotility, spastic colon, pancreatic pain or spasms,pediatric colic, rectal spasms and pain, bladder spasm (overactivebladder), interstitial cystitis, dysmenorrhea, premature labor, pelvicpain, chronic pelvic pain, chronic prostatitis pain, eclampsia,preeclampsia, HELLP syndrome, cystitis pain, irritable bowel syndrome,Cohn's disease, ulcerative colitis, reflux disease, gastritis,gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic,hepato-renal syndrome, appetite suppression, gall bladder pain,inflammation of the esophagus, inflammation of the stomach, inflammationof the colon, kidney pain (from stone, infection, or tumor), enuresis,dysuria, dyspareunia, encopresis, heavy flow periods, frequenturination, prolonged vaginal bleeding, inhibit erections, prevention ofpremature ejaculation, inhibit excessive sweating, ureteral spasms,menstrual cramps, uterine spasms, ovarian pain and spasms, fallopiantube pain and spasms, pediatric asthma, adult asthma, chronicobstructive pulmonary disease (COPD), bronchial mucus, acute bronchitis,asthmatic bronchitis, chronic bronchitis, bronchospasm, cystic fibrosis,inflammation of the lung, emphysema, pleuritic chest pain, intercostalmuscle pain, nerve pain, bronchospasm secondary to intubation andextubation, angina pectoris, cardiac vagal blockage, vasovagal reflexblockage, bradycardia, hypotension, orthostatic hypotension,hypertension, diabetes, shock, septic shock, reduction of blood sugar,inflammation of the pancreas, syncope secondary to vagal or cardiacreasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin,neuralgia, laryngospasm, acute laryngitis, laryngeal pain, chroniclaryngitis, post extubation and intubation laryngospasms, palatalmyoclonus, post-tonsillectomy pain, snoring, allergic rhinitis,vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis,chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups,rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome,fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panicattacks, post-traumatic stress disorder, Tourette's syndrome, focaldystonia, tic doloreaux, bulimia, anxiety, depression, restless legsyndrome, dysautonomia, familial intentional tremor, migraines, autismspectrum, anxiety headaches, insomnia, multiple sclerosis, modulation ofthe reticular activating system, peripheral neuropathy, apraxia, neckand shoulder pain, and Parkinson's disease.

In particular, improvement was reported in over half of the patientstreated in accordance with the above methods, where there were minimumof 5 patients treated for symptoms or conditions associated with thefollowing diseases or disorders, vasovagal reflex blockage, chronicbronchitis, asthmatic bronchitis, hypotension, hypertension, diabetes,bladder spasm, dysmenorrhea, pelvic pain, cystitis pain, enuresis,dysuria, dyspareunia, heavy menstrual flow periods, frequent urination,spasmodic dysphonia, snoring, allergic rhinitis, vasomotor rhinitis,chronic sinusitis, chronic nasal congestion, allergic conjunctivitis,sneezing, hiccups, rhinitis, dysphagia, irritable bowel syndrome,gastritis, appetite suppression, chronic fatigue syndrome, fibromyalgia,anxiety, depression, restless leg syndrome, familial intentional tremor,migraines, autism spectrum, anxiety headaches, insomnia, sleepdisorders, apraxia, and neck and shoulder pain. Similar positive results(i.e., positive results reported for all or more than half of allpatients treated) also were seen with the other listed diseases orclosely-related diseases.

While the methods for treating various diseases associated with thevagus and other cranial nerves have been described in the application inconnection with various embodiments, the scope of the methods is notintended to be limited to the particular embodiments so disclosed. Buton the contrary, the methods are intended to cover such alternatives,modifications, and equivalents, as may be included within the scope andspirit of the below claims.

What is claimed is:
 1. A method for treating a disease associated with aparticular cranial nerve, comprising: administering to an ear canal of asubject in need of such treatment a pharmaceutical composition,comprising: (i) an analgesic and (ii) an anesthetic; wherein saidpharmaceutical composition is administered to the ear canal of thesubject in a concentration sufficient to physiologically alter theactivity of the subject's particular cranial nerve compared to thephysiological activity of that particular cranial nerve in a subject notadministered the pharmaceutical composition.
 2. The method according toclaim 1, wherein the particular cranial nerve is the trigeminal nerve,the facial nerve, the glossopharyngeal nerve, or the vagus nerve.
 3. Themethod according to claim 1, wherein the disease is at least oneselected from the group consisting of: asthma, neurogenic cough, globushystericus, spasmodic dysphonia, gastroesophageal reflux disease, andobesity.
 4. The method according to claim 1, wherein the disease is atleast one selected from the group consisting of: vasovagal reflexblockage, chronic bronchitis, asthmatic bronchitis, hypotension,hypertension, diabetes, bladder spasm, dysmenorrhea, pelvic pain,cystitis pain, enuresis, dysuria, dyspareunia, heavy menstrual flowperiods, frequent urination, spasmodic dysphonia, snoring, allergicrhinitis, vasomotor rhinitis, chronic sinusitis, chronic nasalcongestion, allergic conjunctivitis, sneezing, hiccups, rhinitis,dysphagia, irritable bowel syndrome, gastritis, appetite suppression,chronic fatigue syndrome, fibromyalgia, anxiety, depression, restlessleg syndrome, familial intentional tremor, migraines, autism spectrum,anxiety headaches, insomnia, sleep disorders, apraxia, and neck andshoulder pain.
 5. The method according to claim 1, wherein the analgesicis at least one pyrazolone derivative selected from the group consistingof ampyrone, dipyrone, antipyrine, aminopyrine, and propyphenazone. 6.The method according to claim 1, wherein the analgesic is antipyrine. 7.The method according to claim 1, wherein the anesthetic is at least oneselected from the group consisting benzocaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine, larocaine, piperocaine, propoxycaine,procaine, novocaine, proparacaine, tetracaine, amethocaine, articaine,bupivacaine, cinchocaine, dibucaine, etidocaine, levobupivacaine,lidocaine, lignocaine, mepivacaine, prilocalne, ropivacaine, trimecaine,and pharmaceutically acceptable derivatives thereof.
 8. The methodaccording to claim 1, wherein the anesthetic is benzocaine.
 9. Themethod according to claim 1, wherein the subject does not have an earinfection.
 10. The method according to claim 1, wherein thepharmaceutical composition further comprises one of more of anantibiotic, a vasoconstrictor, glycerin, or acetic acid.
 11. The methodaccording to claim 1, wherein the pharmaceutical composition isadministered in a solution.
 12. The method according to claim 1, whereinthe pharmaceutical composition is administered in a foam.
 13. The methodaccording to claim 1, wherein the analgesic is present in thepharmaceutical composition in a concentration of from 50 to 60 mg per mLand the anesthetic is present in the pharmaceutical composition in aconcentration of from 10 to 20 mg per mL.
 14. The method according toclaim 1, wherein the analgesic is present in the pharmaceuticalcomposition in a concentration of from 50 to 55 mg per mL and theanesthetic is present in the pharmaceutical composition in aconcentration of from 10 to 15 mg per mL.
 15. A method for treatingpost-tonsillectomy pharyngeal pain, comprising: administering to an earcanal of a subject in need of such treatment a pharmaceuticalcomposition, comprising: (i) antipyrine and (ii) benzocaine, whereinsaid subject has had a tonsillectomy within the preceding 168 hoursprior to administering said pharmaceutical composition, and wherein saidpharmaceutical composition is administered to the ear canal of thesubject in a concentration sufficient to physiologically alter theactivity of the subject's vagus nerve compared to the physiologicalactivity of a vagus nerve in a subject not administered thepharmaceutical composition.
 16. The method according to claim 15,wherein the subject has had a tonsillectomy within the preceding 48hours prior to administering said pharmaceutical composition.
 17. Themethod according to claim 15, wherein the pharmaceutical composition isadministered to the ear canal of the subject within 4 hours of thesubject undergoing a tonsillectomy.
 18. A method for treatingpost-adenoidectomy pharyngeal pain, comprising: administering to an earcanal of a subject in need of such treatment a pharmaceuticalcomposition, comprising: (i) antipyrine and (ii) benzocaine, whereinsaid subject has had an adenoidectomy within the preceding 168 hoursprior to administering said pharmaceutical composition, and wherein saidpharmaceutical composition is administered to the ear canal of thesubject in a concentration sufficient to physiologically alter theactivity of the subject's vagus nerve compared to the physiologicalactivity of a vagus nerve in a subject not administered thepharmaceutical composition.
 19. The method according to claim 18,wherein the subject has had an adenoidectomy within the preceding 48hours prior to administering said pharmaceutical composition.
 20. Themethod according to claim 18, wherein the pharmaceutical composition isadministered to the ear canal of the subject within 4 hours of thesubject undergoing an adenoidectomy.
 21. A method for treating asthma,comprising: administering to an ear canal of a subject in need of suchtreatment a pharmaceutical composition, comprising: (i) antipyrine and(ii) benzocaine, wherein said subject has asthma, and wherein saidpharmaceutical composition is administered to the ear canal of thesubject in a concentration sufficient to physiologically alter theactivity of the subject's vagus nerve compared to the physiologicalactivity of a vagus nerve in a subject not administered thepharmaceutical composition.
 22. The method according to claim 21,wherein the subject has suffered an asthma attack within the preceding48 hours.
 23. The method according to claim 21, wherein the subject hassuffered an asthma attack within the preceding 60 minutes.
 24. Themethod according to claim 21, further comprising: monitoring the subjectafter the administration of the pharmaceutical composition and providinga second administration of the pharmaceutical composition uponindication that the subject is suffering from another asthma attack. 25.A method for suppressing appetite, comprising: administering to an earcanal of a subject in need of such treatment a pharmaceuticalcomposition, comprising: (i) antipyrine and (ii) benzocaine, whereinsaid administering occurs at least once during a 24 hour period, andwherein said pharmaceutical composition is administered to the ear canalof the subject in a concentration sufficient to physiologically alterthe activity of the subject's vagus nerve compared to the physiologicalactivity of a vagus nerve in a subject not administered thepharmaceutical composition.
 26. The method according to claim 25,wherein the administering occurs at least 3 times during a 24 hourperiod.
 27. The method according to claim 25, wherein the pharmaceuticalcomposition is administered to the ear canal of the subject immediatelyupon the subject feeling hungry.
 28. The method according to claim 25,wherein the pharmaceutical composition is administered to the ear canalof the subject from about 20 minutes to about 60 minutes prior to a foodbeing consumed by said subject.
 29. The method according to claim 25,wherein the pharmaceutical composition is administered to the ear canalof the subject concurrently with the consumption of a food.